Inflammation is a basic defense mechanism to various infestations, where inflammatory cytokine such as interleukin (IL)-1 and TNF-α (tumor necrosis factor) are known to play important roles. On the basis of the progress of gene analysis of inflammatory cytokines and inflammatory cell adhesion factors, it has been revealed that these cytokines are controlled by a common transcription factor (also called as transcription regulatory factor). This transcription factor is a protein called as NF-κB (also described as NFκB, Nucleic Acids Research, (England), 1986, Vol. 14, No. 20, p. 7897-1914; Cold Spring Harbor Symposia on Quantitative Biology, (USA), 1986, Vol. 51, No. 1, p. 611-624).
This NF-κB is a hetero dimer (also called as complex) of p65 (also called as Rel A) and p50 (also called as NF-κB-1 ), usually binds to I-κB when external stimulation does not exist, and exists in cytoplasm as an inactive type. I-κB is phosphorated by various external stimulations such as oxidative stress, cytokine, lipopolysaccharide, virus, UV, free radical, protein kinase C to become ubiquitin, and then decomposed by proteasome (Genes & Development, (USA), 1995, Vol. 9, No. 22, p. 2723-2735). NF-κB separated from I-κB immediately move into nucleus, and plays a role as a transcription factor by binding to promoter region which has recognition sequence of NF-κB.
In 1997, phosphoenzyme (called as IκB kinase abbreviated as “IKK”), which participates in phosphorylation of I-κB, was identified (Nature, (England), 1997, Vol. 388, p. 548-554; Cell, (USA), 1997, Vol. 90, No. 2, p. 373-383). IKK-α (also called as IKK1) and IKK-β (also called as IKK2) which resemble each other exist among a class of IKK, and they are known to form a complex to bind directly to IκB and phosphorize IκB (Science, (USA), 1997, Vol. 278, p. 866-869; Cell, (USA), 1997, Vol. 91, No. 2, p. 243-252).
Recently, a mechanism except cyclooxygenase inhibition is suggested for aspirin which is a widely used anti-inflammatory agent, which is known to be based on inhibition of NF-κB activation (Science, (USA), 1994, Vol. 265, p. 956-959). Moreover, it was revealed that aspirin regulates release and activation of NF-κB by binding reversibly to IKK-β which is I-κB kinase competing with ATP and by inhibiting phosphorylation of I-κB (Nature, (England), 1998, Vol. 396, p. 77-80). However, a huge amount of aspirin needs to be administered to sufficiently suppress NF-κB activation, and as a result, side effects such as gastrointestinal disorders by prostaglandin synthesis inhibition and increase of bleeding tendency by anticoagulation action are expected to be caused with high probability.
Besides aspirin, some pharmaceuticals are known to have inhibitory action against NF-κB activation. Glucocorticoids (steroid hormones) such as dexamethasone suppress NF-κB activation by binding to their receptors (called as “glucocorticoid receptor,” Science, (USA), 1995, Vol. 270, p. 283-286). However, long term use is not suitable, because they have serious side effects such as aggravation of an infectious disease, generation of peptic ulcer, degradation of bone density, and central action. Leflunomide as an immunosuppressive agent, an isoxazole-type agent, also has NF-κB inhibitory action (Journal of Immunology, (USA), 1999, Vol. 162, No. 4, p. 2095-2102). However, this drug is also not suitable for long term use due to serious side effects. Furthermore, substituted pyrimidine derivatives (Japanese Patent Publication of International Application (KOHYO) No. (Hei) 11-512399, and Journal of Medicinal Chemistry, (USA), 1998, Vol. 41, No. 4, p. 413-419), xanthine derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 9-227561), isoquinoline derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 10-87491), indan derivatives (International Publication WO00/05234 pamphlet), epoxyquinomycin C, D, and their derivatives (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 10-45738, and Bioorganic & Medicinal Chemistry Letters, (England), 2000, Vol. 10, No. 9, p. 865-869) are known as inhibitors against NF-κB activation.
As for salicylamide derivatives, N-phenylsalicylamide derivatives are disclosed as a plant growth inhibitor in the specification of U.S. Pat. No. 4,358,443. Moreover, as medicaments, said derivatives are disclosed as anti-inflammatory agents in the specification of European Patent No. 0,221,211, Japanese Patent Unexamined Publication (KOKAI) No. (Sho) 62-99329, and the specification of U.S. Pat. No. 6,117,859. N-Phenylsalicylamide derivatives having NF-κB inhibitory action are disclosed in the pamphlet of International Publication WO99/65449. However, only a small number of compounds were subjected to measurements of anti-inflammatory activity or inhibitory activity against NF-κB. Moreover, as for a structure of the aniline moiety, studies were made merely on limited kinds of substituents and substituting positions. The pamphlet of International Publication WO02/49632 discloses that hydroxyaryl derivatives including N-arylsalicylamide derivatives have NF-κB inhibitory action. However, the descriptions of O-substituted compounds of hydroxyaryl derivatives are limited to O-acetyl compounds of N-substituted salicylamides. The pamphlet of International Publication WO02/076918 discloses N-phenylsalicylamide derivatives having NF-κB inhibitory action. The pamphlet of International Publication WO02/051397 discloses N-phenylsalicylamide derivatives as inhibitors against the production of cytokines.